A. Biological Activity of Coumarin Derivatives
Anticoagulant and antithrombotic activity of certain natural and synthetic coumarin derivatives is known. See, Murray et al., The Natural Coumarins, Wiley, New York, 1982. Certain coumarin derivatives are also reported as triplet sensitizers (see, Williams et al., Polym. Eng. Sci., 1983, 23, 1022); anti-HIV agents (Spino et al., Bioorg. Med. Chem. Lett., 1998, 8, 3475-78); lipid-lowering agents (Madhavan et al., Bioorg. Med. Chem. Lett., 2003, 13, 2547-51); antioxidants (Kontogiorgis et al., J. Enzyme Inhib. Med. Chem., 2003, 18, 63-69); inhibitors of lipid peroxidation and vasorelaxant agents (Hoult et al., Gen. Pharmac. 1996, 27, 713-22); anti-inflammatory agents (Khan et al., Indian J. Chem., 1993, 32, 817); and free radical scavengers (Mora et al., J. Biochem. Pharmacol., 1990, 40, 793-97). In addition, two naturally-occurring coumarins have been found to exhibit cytotoxicity across a selection of mammalian cancer cell lines (Reutrakul et al., Planta Med., 2003, 69, 1048-51).
Certain coumarin-3-carboxamides have been reported as inhibitors of proteases, including α-chymotrypsin (Pochet et al., Bioorg. Med. Chem. Lett., 2000, 8, 1489-501; Wouters et al., Bioorg. Med. Chem. Lett., 1990, 12, 1109-12; and Mor et al., Biochim. Biophys. Acta, 1990, 1038, 119-24) and human leukocyte elastase (HLE) (Doucet et al., J. Med. Chem., 1999, 42, 4161-71; Egan et al., Drug Metab. Rev., 1990, 22, 503-29; and Nicolaides et al., J. Heterocycl. Chem., 1996, 33, 967)
B. Coumarin-3-sulfonamides
Hoogenboom et al. (J. Org. Chem. (1975), 40(7), 880-3) disclose the compound 2-oxo-N-phenyl-2H-chromene-3-carboxamide. Ismail et al. (Afinidad (2002), 59, 211-15) discloses 2-oxo-N-phenyl-2H-chromene-3-carboxamide derivatives wherein the phenyl ring is substituted by acylsulfonamido. Mandour et al. (Egyptian J. Pharm. Sci. (1995), 36(1-6), 71-85) disclose the synthesis, antimicrobial activity and antiaflatoxigenic activity of 2-oxo-N-phenyl-2H-chromene-3-carboxamide derivatives wherein the coumarin ring system is substituted by nitro. Abd-El-Hafez et al. (Egyptian J. Pharm. Sci. (1994), 35(1-6), 113-26) disclose the preparation and antimicrobial activity of activity of 2-oxo-N-phenyl-2H-chromene-3-carboxamide derivatives wherein the coumarin ring system is substituted by nitro. Abd El-Aleem et al. (Modelling, Measurement & Control, C: Energetics, Chemistry, Earth, Environmental & Biomedical Problems (1995), 47(1), 49-54) and El-Maghraby et al. (Egyptian Journal of Chemistry (1985), 27(4), 459-69) disclose certain coumarin 3,6-disulfonamides. Silvio et al. (Gazz. Chim. Ital., (1967), 97(12), 1749-61) disclose 2-oxo-N-phenyl-2H-chromene-3-carboxamide derivatives wherein the coumarin ring system is substituted at the 4-position by an arylamino group. Merchant et al. (J. Org. Chem., (1957), 22, 884-7) disclose the compound 7-ethyl-6-methoxy-4-methyl-2-oxo-N-phenyl-2H-chromene-3-sulfonamide. Merchant et al. (J. Indian Chem. Soc. (1957), 34, 35-41) discloses the compound 6-nitro-2-oxo-N-phenyl-2H-chromene-3-sulfonamide and the compound 2-oxo-N3,N6-diphenyl-2H-chromene-3,6-disulfonamide.
C. Proliferative Disorders
Extracellular signals received at transmembrane receptors are relayed into the cells via signal transduction pathways (Pelech et al., Science 257:1335 (1992)). Such signalling has been implicated in induction of cell proliferation, differentiation or apoptosis (Davis et al., J. Biol. Chem. 268:14553 (1993)). One such signal transduction pathway is the mitogen activated protein kinase (MAPK) cascade. See, Nishida et al., Trends Biochem. Sci. 18:128 (1993) and Blumer et al., Trends Biochem. Sci. 19:236 (1994). Much of the MAPK pathway is conserved over different species. The most thoroughly studied of the MAPKs are extra cellular signal regulated kinases (ERKs) (Posada et al., Science 255:212 (1992); Biggs III et al., PNAS. USA 89:6295 (1992); and Garner et al., Genes Dev. 6:1280 (1992)) and c-Jun NH2 terminal kinases (JNKs) (Hibi et al., Genes Dev. 7:2135 (1993)). JNKs are members of a class of stress activated protein kinases (SAPK) and are shown to be activated by treatment of cells with UV radiation, pro-inflammatory cytokines and environmental stress (Derijard et al., Cell 1025 (1994)). Activation of ERK has been shown to involve kinase mediated phosphorylation of threonine and tyrosine residues, which signals cell proliferation. In contrast, activation of JNKs leads to cell growth inhibition and apoptosis.
Protein tyrosine kinases are enzymes which catalyze a well defined chemical reaction: the phosphorylation of a tyrosine residue (Hunter et al., Ann. Rev. Biochem. 54:897 (1985)). Receptor tyrosine kinases in particular are attractive targets for drug design since blockers for the substrate domain of these kinases is likely to yield an effective and selective antiproliferative agent. The potential use of protein tyrosine kinase blockers as antiproliferative agents was recognized as early as 1981, when quercetin was suggested as a PTK blocker (Graziani et al., Eur. J. Biochem. 135:583-589 (1983)).
The best understood MAPK pathway involves extracellular signal-regulated kinases which constitute the Ras/Raf/MEK/ERK kinase cascade (Boudewijn et al., Trends Biochem. Sci. 20, 18 (1995)). Once this pathway is activated by different stimuli, MAPK phosphorylates a variety of proteins including several transcription factors which translocate into the nucleus and activate gene transcription. Negative regulation of this pathway could arrest the cascade of these events.
Cancer and other proliferative disorders remain a major unmet medical need. Cancer treatments often comprise surgery, chemotherapeutic treatments, radiation treatment or combinations thereof. Chemotherapeutic treatments for most cancers only delay disease progression rather than providing a cure. Cancers often become refractory to chemotherapy via development of multidrug resistance. Particular cancers are inherently resistant to some classes of chemotherapeutic agents. See DeVita et al, Principles of Cancer Management: Chemotherapy. In: Cancer. Principles and Practice of Oncology, 5th edition, Lippincott-Raven, Philadelphia, New York (1977), pp. 333-347.
Although progress has been made in the range of treatment of proliferative disorders such as cancer, there remains a need to develop new therapeutic agents, particularly agents that target receptor tyrosine kinases and arrest the Ras/Raf/MEK/ERK kinase cascade. Oncoproteins in general, and signal transducing proteins in particular, are likely to be more selective targets for chemotherapy because they represent a subclass of proteins whose activities are essential for cell proliferation, and because their activities are greatly amplified in proliferative diseases.